The critical role of the IL-23/Th17 pathway in mediating the intestinal inflammation observed in inflammatory bowel disease (IBD) has been demonstrated through expression studies in patients with IBD, experimental mouse models of IBD and genetic association studies. A number of independent polymorphisms in IL23R have been identified to confer both risk and protection from developing ulcerative colitis and Crohn's disease, as well as other inflammatory disorders such as ankylosing spondylitis and psoriasis. The most significant of these genetic associations is the R381Q single nucleotide polymorphism (SNP) which results in an amino acid change in the proximal IL23R cytoplasmic tail. This polymorphism leads to a 2-3-fold decreased risk of developing IBD, such that it is enriched in healthy individuals. Studies in our laboratory have identified functional consequences of the R381Q IL23R SNP in both human CD4+ and CD8+ T cells; R381Q IL23R individuals have decreased circulating IL-17- and IL-22- producing CD4+ and CD8+ T cells ex vivo and decreased STAT3 activation to IL-23 stimulation. We hypothesize that this is due to a combination of decreased Th17 and Tc17 cell differentiation and expansion secondary to decreased signaling through R381Q IL23R. This proposal will utilize combined approaches with cells transfected with IL23R polymorphisms and ex vivo cells from individuals with IL23R polymorphisms to define changes in T cell expansion and differentiation, identify altered T cell signaling pathways and determine the compound effects of antigen presenting cell:T cell interactions that ultimately contribute to the decrease in circulating Th17 and Tc17 cells. Addressing these responses in primary human cells is critical to understanding the complexity of the IL-23/Th17 pathway in human immune responses.